Published August 24 in The Journal of Biological Chemistry, their landmark finding is a crucial step in the development of effective diagnostic and therapeutic treatments for venous ulcers and possibly other chronic non-healing wounds, which affect an estimated 8 million Americans every year.
In the study, “Induction of specific micro Ribonucleic acids (miRNAs) inhibits cutaneous wound healing,” Tomic-Canic and her team identified six miRNAs that were abundant in 10 patients with chronic venous ulcers. Replicating the aberration in animal and human models, the researchers found that specific set of miRNAs targets multiple genes critical to healing the painful ulcers that often develop on the legs of patients with venous insufficiency.
“Some of these microRNAs are normally found in skin, but if you have too much of them they cause trouble,” explained Tomic-Canic, who directs the Miller School’s Wound Healing and Regenerative Medicine Research Program. “For example, we found they neutralize signaling of growth factors, like leptin receptor, which is very important in controlling diabetes and obesity. If you eliminate that receptor or its signaling in an animal model, mice develop diabetes or become obese.”
Tomic-Canic believes that aberrant miRNAs also may inhibit healing of chronic diabetic foot ulcers, the world’s leading cause of amputation. She was just awarded a $1.7 million grant from the NIH’s National Institute of Nursing Research to explore that hypothesis. “What we expect is to find some overlap, but we also expect to find something unique to diabetic foot ulcers,” she said.
Recognized as a distinct class of biological regulators in the early 2000s, miRNAs have been implicated in numerous disease states. Short stretches of ribonucleic acids, miRNAs attach to and degrade messengerRNA (mRNA), usually disrupting its translation to protein. Since a single miRNA can target multiple mRNAs, they can affect multiple biological processes, which is what Tomic-Canic and her team determined occurs in patients with venous ulcers.
Using computational analyses of messenger RNA expression profiles, they discovered that the over-expressed miRNAs targeted multiple signaling pathways, delaying both epithelialization, the process by which new cells migrate over the wound bed to close the tissue gap, and the formation of granulation tissue, new connective tissue and tiny blood vessels that form below the surface.
Given that the effectiveness of clinical treatments for venous ulcers (VU) is limited by the lack of understanding of the cellular and molecular pathology that inhibits their healing, Tomic-Canic and her study co-authors are hopeful their discovery will lead to new diagnostic and therapeutic treatments.
“Compared with currently used therapies, the possibility to regulate multiple targets by miRNAs may have a potential to more effectively achieve wound closure,” they wrote. “Our results support that notion that VU-specific miRNAs may serve as a new class of diagnostic and, potentially, therapeutic targets.”
In addition to Tomic-Canic, who was the senior author on the study, other Miller School co-authors included first author Irena Pastar, Ph.D., research assistant professor of dermatology and cutaneous surgery; Olivera Stojadinovic, M.D., research assistant professor of dermatology and cutaneous surgery; Elizabeth A. Lebrun, M.D., first-year dermatology resident; Mayrin Correa Medina, M.D., Ph.D., assistant scientist in the Department of Medicine; Robert S. Kirsner, M.D., Ph.D., professor and vice chair of dermatology and cutaneous surgery and the Stiefel Laboratories Chair; and Joaquin J. Jimenez, M.D., research associate professor of dermatology and cutaneous surgery.
Researchers at the Computational Biology Program at Memorial Sloan-Kettering Cancer Center in New York also contributed.
For her new NIH grant, “Micro-RNA Molecules as Regulators of Diabetic Wound Healing,” Tomic-Canic and her lab will collaborate with the Hussman Institute for Human Genomics to understand the mechanism by which miRNA molecules inhibit the healing of diabetic foot ulcers, with the ultimate goal of developing therapeutics to block the mechanism, and promote healing.
“Chronic, non-healing wounds, such as venous and diabetic foot ulcers, are a serious medical problem, with high morbidly and mortality,” Tomic-Canic said. “The more we know about the molecular mechanisms that contribute to their development, the more we can rationally develop both diagnostic tools and new therapies.”
University of Miami